U.S. patent number 4,605,786 [Application Number 06/563,436] was granted by the patent office on 1986-08-12 for perfluoro ether compound containing perfluorocycloalkyl moiety.
This patent grant is currently assigned to The Green Cross Corporation. Invention is credited to Yoshio Arakawa, Chikara Fukaya, Yoshihisa Inoue, Youichiro Naito, Taizo Ono, Tadakazu Suyama, Koichi Yamauchi, Kazumasa Yokoyama.
United States Patent |
4,605,786 |
Yokoyama , et al. |
August 12, 1986 |
Perfluoro ether compound containing perfluorocycloalkyl moiety
Abstract
A perfluoroether compound having the following formula is useful
as a thermostable, inert solvent and inter alia as an oxygen
carrier in an artificial blood or infusion fluid. ##STR1## wherein
Rf.sub.1 and Rf.sub.2 are different from each other and are
selected from the group of a C.sub.1 or C.sub.3 perfluoroalkyl
group which may be interrupted by an oxygen atom, and a C.sub.5
-C.sub.7 perfluorocycloalkyl group, and n and n' are zero or an
integer of 1; one of Rf.sub.1 and Rf.sub.2 being the C.sub.5
-C.sub.7 perfluorocycloalkyl group and the total number of carbon
atoms being 9-11 inclusive.
Inventors: |
Yokoyama; Kazumasa (Toyonaka,
JP), Inoue; Yoshihisa (Kyoto, JP), Ono;
Taizo (Tokyo, JP), Fukaya; Chikara (Osaka,
JP), Arakawa; Yoshio (Suita, JP), Naito;
Youichiro (Hirakata, JP), Yamauchi; Koichi
(Sakai, JP), Suyama; Tadakazu (Kyoto, JP) |
Assignee: |
The Green Cross Corporation
(Osaka, JP)
|
Family
ID: |
16825956 |
Appl.
No.: |
06/563,436 |
Filed: |
December 20, 1983 |
Foreign Application Priority Data
|
|
|
|
|
Dec 21, 1982 [JP] |
|
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57-225226 |
|
Current U.S.
Class: |
568/669; 252/364;
514/832 |
Current CPC
Class: |
C07C
43/123 (20130101); C07C 43/313 (20130101); C07C
43/192 (20130101); Y10S 514/832 (20130101) |
Current International
Class: |
C07C
43/192 (20060101); C07C 43/12 (20060101); C07C
43/313 (20060101); C07C 43/00 (20060101); C07C
043/12 () |
Field of
Search: |
;568/669,683 ;424/339
;514/832 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Cady, Proceedings of the Chemical Society (London) Apr. 1960, pp.
133 & 136. .
Riess et al. "Perfluoro Compounds as Blood Substitutes", Int'n. Ed.
in English, Angewandte Chemie, vol. 17, No. 9, Sep. 1978, pp.
621-700..
|
Primary Examiner: Helfin; Bernard
Attorney, Agent or Firm: Cushman, Darby & Cushman
Claims
What is claimed is:
1. A perfluoro ether compound represented by the formula ##STR33##
wherein Rf.sub.1 and Rf.sub.2 are different from each other and are
selected from a C.sub.1 to C.sub.3 perfluoroalkyl group, which may
be interrupted by an oxygen atom, and a C.sub.5 -C.sub.7
perfluorocycloalkyl group, and n and n' are zero or an integer of
1; provided that one of Rf.sub.1 and Rf.sub.2 is C.sub.5 -C.sub.7
perfluorocycloalkyl group and the the total number of carbon atoms
is 9-11 inclusive.
2. The perfluoro ether compound of claim 1, having the formula (I),
in which Rf.sub.1 is a perfluoro C.sub.5 -C.sub.7 cycloalkyl group,
and Rf.sub.2 is a C.sub.1 to C.sub.3 perfluoroalkyl group which may
be interrupted by an oxygen atom.
3. The perfluoro ether compound of claim 1, having the formula (I),
in which Rf.sub.1 is a C.sub.1 or C.sub.3 perfluoroalkyl group
which may be interrupted by an oxygen atom, and Rf.sub.2 is a
perfluoro C.sub.5 -C.sub.7 cycloalkyl group.
4. The perfluoroether compound of claim 1, in which the perfluoro
C.sub.5 -C.sub.7 cycloalkyl group is selected from the group
consisting of perfluorocyclopentyl, perfluorocyclohexyl and
perfluoroheptyl groups.
5. The perfluoro ether compound of claim 1, in which the C.sub.1 to
C.sub.3 perfluoroalkyl group is selected from the group consisting
of perfluoro methyl, perfluoro ethyl, perfluoro n-propyl and
perfluoro isopropyl groups.
6. The perfluoro ether compound of claim 1, in which the oxygen
atom-interrupted C.sub.1 to C.sub.3 perfluoroalkyl group is
selected from the group consisting of perfluoro methoxy, perfluoro
methoxymethyl, perfluoro methoxyethyl and perfluoroethoxymethyl
groups.
Description
This invention relates to a novel perfluoro ether compound, and
more particularly to a perfluoro ether compound having a
perfluorocycloalkyl moiety in the molecule, which is useful as a
thermostable, inert solvent as well as an oxygen carrier in an
artificial blood or in an infusion fluid.
The perfluoro ether compound of the present invention is
represented by the formula ##STR2## wherein Rf.sub.1 and Rf.sub.2
are different from each other and are selected from the group of a
C.sub.1 to C.sub.3 perfluoroalkyl group which may be interrupted by
an oxygen atom, and a C.sub.5 -C.sub.7 perfluorocycloalkyl group,
and n and n' are zero or an integer of 1; one of Rf.sub.1 and
Rf.sub.2 being the C.sub.5 -C.sub.7 perfluorocycloalkyl group and
the total number of carbon atoms being 9-11 inclusive.
The C.sub.5 -C.sub.7 perfluoroalkyl group denoted by Rf.sub.1 and
Rf.sub.2 is cyclopentyl, cyclohexyl or cycloheptyl group which is
all perfluorinated. The perfluorocycloalkyl group is essentially
present only one in the molecule and links to ##STR3## or to --O--
optionally through --CF.sub.2 -- in the molecule. When one of the
Rf.sub.1 and Rf.sub.2 is the perfluorocycloalkyl group the other is
C.sub.2 -C.sub.3 perfluoroalkyl which may be interrupted by an
oxygen atom.
The C.sub.1 to C.sub.3 perfluoroalkyl group containined in the
present perfluoro ether compound is exemplified as perfluoro
methyl, perfluoroethyl, perfluoro n-propyl and perfluoroisopropyl
which may be interrupted by an oxygen atom so as to form perfluoro
methoxymethyl, perfluoro methoxyethyl or perfluoro
ethoxymethyl.
The perfluoro ether compound of the invention should have 9-11
carbon atoms in the molecule for giving good artificial blood in
which the perfluoroether compound is emulsified in a
physiologically acceptable aqueous medium.
The perfluoro ether compound (I) can be prepared, for example, by
the fluorination, particularly the electrochemical fluorination, of
a perhydrocompound corresponding to said compound (I) or of a
partial hydro compound (I) or of a partial hydro compound
corresponding to said compound (I). The partial hydro compound to
be used preferably in a compound represented by the formula
##STR4## wherein R and R' denote a perhydro group corresponding to
Rf.sub.1 and Rf.sub.2 of the formula (I), respectively; n and n'
have the same meaning as above. When the method of electrochemical
fluorination of the compound (II) is used, the perfluoro ether
compound (I) can be obtained in a high yield even in the absence of
an electric conductivity improver often needed for conventional
electrochemical fluorination. Moreover, because of the presence of
trifluoromethyl groups which are strong electron attractive groups
in the compound (II), the ether linkage is trong and hardly broken,
the amount of by-product formed by bond cleavage is small, and the
perfluoro ether compound (I) is obtained with high purity.
The electrochemical fluorination of a perhydro compound or a
partial hydro compound (II) corresponding to the above-mentioned
perfluoro ether compound (I) is usually carried out in anhydrous
hydrofluoric acid. Preferably, the starting compound is used in an
amount corresponding to 0.1 to 0.3 mole for 1 liter of hydrofluoric
acid. The electrolytic cell to be used may be those which are
conventionally employed in the field of electrochemical
fluorination. The electrochemical fluorination is normally
performed at a current density of 0.2 to 3.0 A/dm.sup.2 and a bath
temperature of 3.degree. to 10.degree. C. and, in the case of
batchwise operation, preferably carried out until the electrolytic
voltage reaches at least 8 V. The addition of an electric
conductivity improver (such as sodium fluoride) is optional.
The perfluoro ether compound (I) can be separated, when the
starting compound (II) was fluorinated, as shown in the following
example. Since most of the said compound (II) remains in the
electrolytic cell and separates from hydrogen fluoride to form a
lower layer, it is withdrawn from the cell after completion of the
electrochemical fluorination. The mixture of the said compound (II)
and the rearrangement product thereof is stirred under heating with
an alkali-amine (sodium hydroxide-diisobutylamine etc.) mixture,
washed, if necessary, with a potassium iodide-acetone mixture, and
then separated by fractional distillation, preparative-scale gas
chromatography etc.
The compound (II) is substantially known already, and is prepared
by the reaction of a compound represented by the formula ##STR5##
wherein R and n are the same as above, with a compound represented
by the formula
wherein X denotes a halogen atom such as chlorine or bromine; n' is
the same as above, or by alkylating the former compound with an
alkylsulfate such as dimethylsulfate or diethylsulfate.
The compound (III) may be obtained by using hexafluoroacetone
according to the conventional method described, for example, by I.
L. Knunyants et al. (Izv. Akad. Nauk SSSR Otd. Khim. Nauk, 1962, p.
684) or W. A. Sheppard [J. Am. Chem. Soc., 87, 2410 (1965)].
Since the perfluoro ether compound (I) of this invention not only
can dissolve a large amount of oxygen and is chemically and
biologically inert, but can be excreted rapidly from the body, it
can form, for example, an aqueous emulsion containing 5 to 50,
preferably 10 to 40, % (W/V) of the compound (I) to be used as an
oxygen carrier in an artificial blood or in an infusion fluid for
men and other mammals such as dogs, cats, cattle, mice, rats and
guinea pigs.
The symbol "% (W/V)" referred to herein means the amount of the
material by weight (gram) based on 100 ml of the resulting
emulsion.
In the preparation of the emulsion mentioned above, there is used,
as an emulsifier, a high molecular nonionic surfactant and/or
phospholipids in an added amount of 1 to 5% (W/V).
As the medium for the emulsion, a physiologically acceptable
aqueous solution is employed. If necessary, there may be added
thereto such materials as glycerol to provide the desired
isotonicity, and such plasma expanders as HES or dextran to
regulate the colloid osmotic pressure of the emulsion.
The emulsion can be prepared by mixing the above-mentioned
ingredients and homogenizing the mixture by means of, for example,
a high-pressure jet type homogenizer until the particle diameters
become 0.05 to 0.3 .mu.m, preferably less than 0.2 .mu.m.
EXAMPLE 1
Into an electrolytic cell made of Monel metal with an inner volume
of 1.5 , which was provided with electrode plates (six plates as
anode and seven plates as cathode) made of nickel (purity: 99.6% or
higher) arranged alternately with an inter-electrode distance of
1.7-2.0 mm, the effective anode surface area being 10.5 dm.sup.2,
and with a reflux condenser made of copper at the upper part of the
cell, was introduced 1.2 l of anhydrous hydrogen fluoride, and
trace amounts of impurities were removed by preliminary
electrolysis. Then, 0.16 mol of
[1,1-bis(trifluoromethyl)butoxy]cyclopentane ##STR6## was
introduced into the anhydrous hydrogen fluoride, and electrolysis
was carried out, while introducing nitrogen gas from the bottom of
the cell at a rate of 100 ml/min., under the conditions of anode
current density of 0.3-1.0 A/dm.sup.2, voltage 5.4-6.6 V and
solution temperature of 3.degree.-8.degree. C. until the
ampere-hours amounted to 154. No attempts was made to collect
volatile products formed by a bond breaking reaction, which would
give more yields of the whole products. After completion of the
electrolysis, the contents of the cell separated into the upper
layer of hydrogen fluoride and the lower layer of fluorocarbons.
The lower layer was drained through the bottom of the cell, weighed
73.2 g (80.8% crude yield).
To the fluorocarbons thus separated, were added equal volumes of
70% aqueous potassium hydroxide solution and diisobutylamine, and
the resulting mixture was refluxed for about three days. The
reaction mixture was then mixed with an equal volume of water,
cooled in an ice bath, and filtered by suction. The perfluoro
compound sedimented as the lowermost layer were separated in a
separatory funnel, washed successively with dilute sulfuric acid,
concentrated sulfuric acid, saturated aqueous sodium hydrogen
carbonate solution, water, 90% aqueous acetone solution containing
3% of potassium iodide, and water to yield 58 g of a transparent
perfluoro compound.
The thus obtained perfluoro compound free from contaminants
containing protons was subjected to simple distillation to give
47.1 g (52.0% yield) of a compound boiling at
145.degree.-155.degree. C.
The compound obtained above was subjected to preparative-scale gas
chromatography to collect the desired product. This product was
analyzed by spectroscopy (IR, 19F-NMR, MS), and was confirmed to be
the objective compound, perfluoro[(1,1-dimethylbutoxy)cyclopentane]
##STR7## which is shown in Table 1 below as compound No. 12.
EXAMPLE 2
Under the same conditions as in Example 1, except for the addition
of an electricity conductivity improver,
2-phenyl-2-methoxy-1,1,1,3,3,3-hexafluoropropane, ##STR8## was
fluorinated. Almost no polymerization, which is characteristic of
electrochemical fluorination of compounds having an aromatic
nucleus, was observed. The reaction product was, after alkali-amine
treatment and potassium iodide-acetone treatment, subjected to
simple distillation to give a product in a 53.2% yield. The
isolated compound by using preparative-scale gas chromatography was
analyzed by spectroscopy (IR, 19F-NMR, MS), and was confirmed to be
the objective compound,
perfluoro[(1-methoxy-1-methylethyl)cyclphexane]of the formula,
##STR9## which is shown as Compound No. 1 in Table 1 below.
A series of other perfluoro ether compounds was synthesized in
exactly the same manner or in the same manner except the addition
of sodium fluoride as that described above. Each product was, after
purification and fractional distillation, isolated by using
preparative-scale gas chromatography and confirmed to be the
objective compound (I) upon analysis by spectroscopy (IR, 19F-NMR,
MS). The name, the structural formula, and the boiling point of
each of the objective compounds (I) were as shown in the following
Table 1.
Each of the structural formula shown in Table 1 implies that all
the carbon atoms are saturated with fluorine atoms, and the
fluorocarbon groups therein are abbreviated.
For example, the formula ##STR10## indicates in its exact meaning
the formula of the product of Example 2.
TABLE 1 ______________________________________ Com- Boiling pound
Structural pt. No. Name formula (.degree.C.)
______________________________________ 1 Perfluoro[(1-methoxy-
1-methylethyl)cyclo- hexane] ##STR11## 130- 140 2
Perfluoro[(1-ethoxy- 1-methylethyl)cyclo- hexane] ##STR12## 144-
154 3 Perfluoro{[1-methoxy- methoxy)-1-methylethyl]- cyclohexane]
##STR13## 146- 157 4 Perfluoro[(1-methoxy-1- methylethyl)-
cycloheptane] ##STR14## 144- 154 5 Perfluoro[2-methoxy-
2-methylpropyl)- cyclopentane] ##STR15## 145- 155 6
Perfluoro[(1-ethoxy-1- methylethyl)cyclo- heptane] ##STR16## 130-
139 7 Perfluoro{[1-methoxy- methoxy)-1-methylethyl]- cyclopentane]
##STR17## 130- 139 8 Perfluoro[(1-methoxy- 1-methylethyl)cyclo-
pentane] ##STR18## 114- 122 9 Perfluoro[1-methyl-1-
propoxyethyl)cyclo- pentane] ##STR19## 145- 156 10
Perfluoro[(1-methyl-1- isopropoxyethyl)- cyclopentane] ##STR20##
144- 154 11 Perfluoro{[1-(ethoxy- methoxy)-1-methyl-
ethyl]cyclopentane] ##STR21## 147- 158 12 Perfluoro[(1,1-di-
methylbutoxy)cyclo- pentane] ##STR22## 145- 155 13
Perfluoro[(1,1,2-tri- methylpropoxy)cyclo- pentane] ##STR23## 145-
155 14 Perfluoro[(2-ethoxy- 1,1-dimethylethoxy)- cyclopentane]
##STR24## 149- 159 15 Perfluoro[(1,1-di- methylpropoxy)cyclo-
pentane] ##STR25## 130- 140 16 Perfluoro[2-methoxy-
1,1-dimethylethoxy)- cyclopentane] ##STR26## 132- 142 17
Perfluoro[(1,1-di- methylpropoxy)cyclo- hexane ##STR27## 146- 155
18 Perfluoro[(2-methoxy- 1,1-dimethylethoxy)- cyclohexane ##STR28##
148- 157 19 Perfluoro(tert-butoxy- cyclohexane) ##STR29## 129- 139
20 Perfluoro(tert- butoxycyclopentane) ##STR30## 114- 124 21
Perfluoro(tert- butoxycyclopentane) ##STR31## 146- 155 22
Perfluoro[tert-butoxy- methyl)cyclo- hexane ##STR32## 147- 156
______________________________________
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